The Dmbt1 gene encodes alternatively spliced glycoproteins that are either membrane associated or secreted epithelial products. Functions proposed for Dmbt1 include it being a tumor-suppressor, having roles in innate immune defense and inflammation, and being a Golgi sorting receptor in the exocrine pancreas. The heavily sulfated membrane glycoprotein Muclin (mucin-like glycoprotein) is a Dmbt1 product that is strongly expressed in organs of the gastrointestinal (GI) system. To explore Muclin's functions in the GI system the Dmbt1 gene was targeted to produce Muclin-deficient mice. Muclin-deficient mice have normal body weight gain and are fertile. The Muclin-deficient mice did not develop GI tumors, even when crossed with mice lacking the known tumor suppressor p53. When colitis was induced by dextran sulfate sodium, there was not a significant difference in disease severity in Muclin-deficient mice. Also, when acute pancreatitis was induced with supraphysiological caerulein there was no difference in disease severity in the Muclin-deficient mice. Exocrine pancreatic function was impaired as measured by attenuated neuro-hormonal stimulated amylase release from Muclin-deficient acinar cells. Also, by [³⁵S]met/cys pulse-chase analysis, traffic of newly synthesized protein to the stimulus-releasable pool was significantly retarded in Muclin-deficient cells as compared to wild type. Thus, Muclin-deficiency impairs trafficking of regulated proteins to a stimulus-releasable pool in the exocrine pancreas.